Wang Shuo, Zeng Heng, Xie Xue-Jiao, Tao Yong-Kang, He Xiaochen, Roman Richard J, Aschner Judy L, Chen Jian-Xiong
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.
School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
Oncotarget. 2016 Sep 13;7(37):58848-58861. doi: 10.18632/oncotarget.11585.
Pulmonary arterial hypertension (PAH) is a leading cause of heart failure. Although pulmonary endothelial dysfunction plays a crucial role in the progression of the PAH, the underlying mechanisms are poorly understood. The HIF-α hydroxylase system is a key player in the regulation of vascular remodeling. Knockout of HIF-2α has been reported to cause pulmonary hypertension. The present study examined the role of endothelial cell specific prolyl hydroxylase-2 (PHD2) in the development of PAH and pulmonary vascular remodeling. The PHD2f/f mouse was crossbred with VE-Cadherin-Cre promoter mouse to generate an endothelial specific PHD2 knockout (Cdh5-Cre-PHD2ECKO) mouse. Pulmonary arterial pressure and the size of the right ventricle was significantly elevated in the PHD2ECKO mice relative to the PHD2f/f controls. Knockout of PHD2 in EC was associated with vascular remodeling, as evidenced by an increase in pulmonary arterial media to lumen ratio and number of muscularized arterioles. The pericyte coverage and vascular smooth muscle cells were also significantly increased in the PA. The increase in vascular pericytes was associated with elevated expression of fibroblast specific protein-1 (FSP-1). Moreover, perivascular interstitial fibrosis of pulmonary arteries was significantly increased in the PHD2ECKO mice. Mechanistically, knockout of PHD2 in EC increased the expression of Notch3 and transforming growth factor (TGF-β) in the lung tissue. We conclude that the expression of PHD2 in endothelial cells plays a critical role in preventing pulmonary arterial remodeling in mice. Increased Notch3/TGF-β signaling and excessive pericyte coverage may be contributing to the development of PAH following deletion of endothelial PHD2.
肺动脉高压（PAH）是心力衰竭的主要原因。尽管肺内皮功能障碍在PAH的进展中起关键作用，但其潜在机制仍知之甚少。HIF-α羟化酶系统是血管重塑调节中的关键参与者。据报道，敲除HIF-2α会导致肺动脉高压。本研究探讨了内皮细胞特异性脯氨酰羟化酶-2（PHD2）在PAH发生发展及肺血管重塑中的作用。将PHD2f/f小鼠与VE-钙黏蛋白-Cre启动子小鼠杂交，以产生内皮特异性PHD2敲除（Cdh5-Cre-PHD2ECKO）小鼠。与PHD2f/f对照相比，PHD2ECKO小鼠的肺动脉压和右心室大小显著升高。内皮细胞中敲除PHD2与血管重塑有关，肺动脉中膜与管腔比值增加以及肌化小动脉数量增加证明了这一点。肺中周细胞覆盖和血管平滑肌细胞也显著增加。血管周细胞的增加与成纤维细胞特异性蛋白-1（FSP-1）表达升高有关。此外，PHD2ECKO小鼠肺动脉的血管周围间质纤维化显著增加。机制上，内皮细胞中敲除PHD2会增加肺组织中Notch3和转化生长因子（TGF-β）的表达。我们得出结论，内皮细胞中PHD2的表达在预防小鼠肺动脉重塑中起关键作用。Notch3/TGF-β信号增加和周细胞过度覆盖可能是内皮PHD2缺失后PAH发生发展的原因。
